This invention relates to novel chemical compounds and their use as pharmaceuticals.
It is known that excitatory neurotransmission in the mammalian central nervous system is primarily mediated by the amino acid, L-glutamate, acting on ionotropic and metabotropic receptors, and compounds that modify neurotransmission by interaction with these receptors are of interest for their potential use in the treatment of disorders of the central nervous system.
This invention relates to use of a compound of formula I 
in which,
R1, R2 and R3 are independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C10)cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl(C1-C6)alkyl, unsubstituted or substituted aryl(C2-C6)alkenyl, halo, carboxy, (C1-C6)alkoxycarbonyl or xe2x80x94(CH2)mxe2x80x94OH, wherein m is 1, 2 or 3;
- - -  indicates a single or a double bond;
X and Y are each independently hydrogen, or X and Y together represent a bridge of the formula xe2x80x94(CH2)nxe2x80x94, where n is 1 or 2;
A1 and A2 are each independently an unsubstituted or substituted aryl;
Z is xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94CH2xe2x80x94;
provided that, when Z is xe2x80x94COxe2x80x94, A1 is not 3,4,5-trimethoxyphenyl;
or a pharmaceutically-acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of a condition indicating the administration of a selective mnGluR1 antagonist.
The present invention also provides a method of treating an animal, including a human, suffering from or susceptible to a condition indicating the administration of a selective mnGluR1 antagonist which comprises administering a compound as defined above or a pharmaceutically acceptable salt or ester thereof. The compounds of the invention have been found to be active in tests indicative of their use in the treatment of diseases of the central nervous system such as neurological diseases, for example, neurodegenerative diseases, and as antipsychotic, anticonvulsant, analgesic and anti-emetic agents.
In the above general formula, a (C1-C6)alkyl group can be straight or branched chain, such as, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl, and is preferably methyl or ethyl. A (C2-C6)alkenyl group includes, for example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and. isopropenyl, and an alkenyl group can contain more than one double bond and, in addition, one or more triple bonds. A preferred alkenyl group is of the formula Rxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94 where Rxe2x80x2 is C1-C4 alkyl.
A (C3-C10)cycloalkyl group is preferably, for example, cyclopropyl, cyclobutyl; cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two C1-C4 alkyl, for example methyl, or ethyl substituents.
An unsubstituted or substituted aryl group includes aromatic and heteroaromatic rings, such as phenyl, napththalene, benzodioxan, thiophene, furan, pyrrole, imidazole, thiadiazole, pyridine, oxazole, benzofuran, indole and thiazole. An unsubstituted or substituted aryl(C1-C6)alkyl group is one such aryl group linked through an alkylene chain, for example, aryl- (CH2)n where n is 1 to 6, and a most preferred example is benzyl. An unsubstituted or substituted aryl(C2-C6)alkenyl is one such aryl group linked through an alkenylene chain derived from an alkenyl group as defined above, and preferably of the formula arly- (CH2)nCHxe2x95x90CHxe2x80x94 where n is 1 to 4.
In the above general formula, when an aryl group is substituted, it is substituted with, for example, one or ore substituents, preferably 1 to 3 substituents, selected from (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, (C1-C6)alkylthio, halo, trifluoromethyl, cyano, nitro, amino, (C1-C6)alkylamino, (C1-C6)acylamino, xe2x80x94NHCOOxe2x80x94(C1-C6)alkyl, xe2x80x94NHSO2(C1-C6)alkyl (C1-C6)alkylsulphone or amide.
A halo includes for example fluoro, chloro and bromo, preferably fluoro or chloro.
A (C1-C6)alkoxy or a (C1-C6)alkylthio is an alkyl group linked to an oxygen or a sulphur atom, where the alkyl is as defined above. A (C1-C6)alkoxy or a (C1-C6)alkylthio group includes for example methoxy, ethoxy, methylthio or ethylthio.
A (C1-C6)alkylamino, is an alkyl group linked to a xe2x80x94NHxe2x80x94 group, where the alkyl is as defined above. A (C1-C6)alkylamino group includes for example methylamino or ethylamino.
A (C1-C6)acylamino group is an alkyl group linked to an amide group, where the alkyl is as defined above, and is preferably of the formula Rxe2x80x94COxe2x80x94NHxe2x80x94 where R is (C1-C5)alkyl.
A (C1-C6)acylamino group includes for example acetamido.
A (C1-C6)alkoxycarbonyl group is an alkoxy group linked to a carbonyl group, where the alkoxy group is as defined above. A (C1-C6)alkoxycarbonyl group includes for example methoxycarbonyl.
A xe2x80x94NHCOOxe2x80x94(C1-C6)alkyl, or a xe2x80x94NHSO2(C1-C6)alkyl group is an alkyl group linked to a group of the formula xe2x80x94NHCOOxe2x80x94 or a xe2x80x94NHSO2xe2x80x94, where the alkyl is as defined above. A xe2x80x94NHCOOxe2x80x94(C1-C6)alkyl, or a xe2x80x94NHSO2(C1-C6)alkyl group includes for example methylcarbamoyl, or methylsulfonylamino.
A (C1-C6)alkylsulphone group is an alkyl group linked to a sulphone group, where the alkyl is as defined above. A (C1-C6)alkylsulphone group includes for example methylsulphone or ethylsulphone. It will be understood that - - -  in formula (I) indicates that the bond can be either a single or a double bond. A preferred group of compounds according to formula (I) is one in which - - -  indicates a double bond.
It is preferred that R1, R2 and R3 are each independently hydrogen, (C1-C6)alkyl, especially methyl or ethyl, carboxy or xe2x80x94(CH2)mxe2x80x94OH, wherein m is 1, 2 or 3.
It is also preferred that X and Y are each independently hydrogen.
It is especially preferred that A1 is a phenyl substituted 1 to 3 times with a amino, (C1-C6)acylamino, especially acetamido or a xe2x80x94NHCOOxe2x80x94(C1-C6)alkyl, especially methylcarbamoyl. It is also preferred that A2 is a phenyl substituted 1 to 3 times with a (C1-C6)alkoxy, especially ethoxy or ethoxy.
It is further preferred that Z is xe2x80x94SO2xe2x80x94 or xe2x80x94CH2xe2x80x94, especially xe2x80x94SO2xe2x80x94.
Especially preferred compounds are of the formula 
wherein,
R1 and R3 are each independently hydrogen, or (C1-C6)alkyl, especially methyl;
R4 is amino, (C1-C6)acylamino, especially acetamide, or a xe2x80x94NHCOOxe2x80x94(C1-C6) alkyl, especially methylcarbamoyl;
R5 is (C1-C6)alkoxy, especially methoxy or ethoxy, and
p and q are each independently 1 or 2, especially 1;
or a pharmaceutically-acceptable salt or ester thereof.
It will be appreciated that when P is other than one, then the R5 substituents can be different. Similarly. when q is other than one, then the R4 substituents can be different. It is further preferred that the R4 substituent is in the 4 position of the phenyl ring.
Particularly useful compounds of invention are 2-(4-Acetamidobenzenesulphonyl)-3,6-dihydro-3, 5-dimethyl-6-(4-methoxyphenyl)-2H-1,2-oxazine, 2-(4-Acetamidobenzenesulphonyl)-3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H1,2-oxazine, and 3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2-(4-methylcarbamoylbenzenesulphonyl)-2H-1,2-oxazine, or a pharmaceutically-acceptable salt or ester thereof.
It will also be understood that esters of the compounds of the invention can be prepared and such esters are included in the invention. They can be aliphatic or aromatic such as, for example, alkyl and phenolic esters. The most preferred esters are alkyl esters derived from C1-C6 alkanols, especially methyl and ethyl esters.
It will also be understood that salts of the compounds of the invention can be prepared and such salts are included in the invention. They can be any of the well known acid addition salts. Acid addition salts are preferably the pharmaceutically-acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example glycollic, maleic, fumaric, malic, tartaric, citric, salicyclic or o-acetoxybenzoic acids, or organic sulphonic acids, methane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2-sulphonic acids.
In addition to pharmaceutically-acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically-acceptable, salts, or are useful for identification, characterisation or purification.
It will be appreciated that the compounds of the invention can contain 1, 2, 3 or 4 asymmetric carbon atoms as indicated by the asterisks in formula (III), and these gives rise to enantiomers. The compounds can be prepared as racemates or as enantiomers, and individual enantiomers can be isolated from racemates by conventional techniques if so desired. Such racemates and individual enantiomers form part of the present invention. 
It is preferred that when - - -  is a double bond, the remaining two asymmetric carbons are in a cis disposition regarding R1 and A2, as shown in formulae (IV)a and (IV)b. 
The invention also includes a process for the production of compounds of formula (I), which comprises reacting a compound of formula 
in the presence of a compound A1xe2x80x94Zxe2x80x94L, wherein A1, A2, R1, R2, R3, X, Y and Z have the values defined above, and L is a leaving group, such as for example chloro, bromo or iodo. It is preferred that the intermediate (Ia) is n the form of an acid addition salt. This acid addition salt is preferably addition salt with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, maleic, fumaric, malic, or organic sulphonic acids, methane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2-sulphonic acids.
The reaction is carried out preferably at a range of temperatures varying from 0xc2x0 C. up to reflux. It is also preferred that the reaction is carried out in the presence of a suitable base such as for example triethylamine. It is further preferred that the reaction is carried out in a suitable organic solvent such as dichloromethane. The intermediates A1xe2x80x94Zxe2x80x94L are readily available or are synthesized by conventional methods. The intermediate (Ia) is prepared via Diels Alder reaction of compounds of formula 
with a compound of formula Oxe2x95x90Nxe2x80x94Q, wherein A2, R1, R2, R3, X and Y have the values defined above, and Q is for example xe2x80x94COOtBu or 1-chlorocyclohexyl.
The Diels Alder reaction is carried out preferably at a range of temperatures varying from 0xc2x0 C. up to reflux. It is also preferred that the reaction is carried out in a suitable organic solvent such as diethylether, dichloromethane or ethanol. The reagents Oxe2x95x90Nxe2x80x94Q are readily available. The intermediate (Ib) is prepared by conventional methods, such as for example by dehydrating compounds of formula 
wherein A2, R1, R2, R3, X and Y have the values defined above.
The dehydration reaction is carried out preferably at a range of temperatures varying from 80xc2x0 C. up to 150xc2x0 C., and more preferably under vacuum, such as for example at 4 mbar. It is also preferred that the reaction is-carried out in the presence of a suitable dehydrating agent such as for example potassium hydrogen sulphate. It is further preferred that the reaction is carried out in the presence of a polymerisation inhibitor such as for example hydroquinone.
The intermediate (Ic) is prepared by conventional methods, such as for example reacting-compounds of formula (Id) with organometalic compounds of formula (Ie) 
wherein A2, R1, R21 R3, X and Y have the values defined above. The reagent (Ie) is an organometalic compound, such as an organolithium where M is lithium, or a grignard, where M is a(L1Mg) group, wherein L1 is a halo, such as for example chloro, bromo or iodo.
This reaction is carried out preferably at a range of temperatures varying from xe2x88x9220xc2x0 C. up to reflux. It is also preferred that the reaction is carried out in a suitable solvent such as for example diethylether.
The intermediates (Id) and (Ie) are readily available or are synthesized by conventional methods.
An alternative method for the synthesis of intermediate (Ic) is via a Wittig reaction. Compounds of formula (Id) are reacted with compounds of formula (If) 
wherein R1 and X have the values defined above, and Mxe2x80x2 is a group of the formulaxe2x88x92(PO)xe2x80x94(ORxe2x80x3)2 or xe2x80x94P(Rxe2x80x3)3L2xe2x80x2, wherein Rxe2x80x3 is a C1-C6 alkyl and L2 is a halo, such as for example chloro, bromo or iodo.
This reaction is carried out preferably at a range of temperatures varying from xe2x88x9260xc2x0 C. up to reflux. It is also preferred that the reaction as carried out in a suitable solvent such as for example tetrahydrofuran. It is further preferred that the reaction is carried out in the presence of a suitable base such as for example, n-butyllithium or sodium hydride.
The intermediate (If) is readily available or is synthesized by conventional methods.
The present invention also provides novel intermediates of formula 
wherein A1 , A2, R1, R21, R3, X and Y have the values defined above.
It will be appreciated that the production of compounds of formula (I) and any novel intermediates, may be optionally followed by the formation of esters or salts thereof.
According to a further aspect of the invention the compounds described above have pharmaceutical activity. They have been shown to possess affinity for glutamate receptors.
Excitatory amino acid or glutamate receptors are subdivided into two types, ionotropic and metabotropic. Ionotropic glutamate receptors are ligand gated ion channels that are composed of multiple subunit proteins forming multimeric complexes. Ionotropic glutamate receptors are selectively activated by the agonists N-methyl-D-aspartate, AMPA, and kainate (Sommer B. and Seeburg P. H., Trends Pharmacol. Sci. 13: 291-296, 1993). Metabotropic glutamate receptors are a family of G-protein coupled receptors which are coupled to increases in phosphoinositide hydrolysis and decreases in cAMP formation. (Schoepp D. D. and Conn J. P., Trends Pharmacol. Sci. 14: 13-20, 1993).
The compounds of the present invention are active in a screen for activity in metabotropic receptors as described in Kingston et al, Neuropharmacology 1995, 34, 887-894. They have been shown to possess affinity for group 1 metabotropic receptors, especially mnGluR1 receptors. They are particularly useful as selective mGluR1 antagonists.
The compounds of the invention are thus indicated for use in the treatment of disorders of the central nervous system such as cognitive impairment and acute neurodegenerative diseases, for example stroke, cerebral ischaemia and head and spinal cord trauma, and chronic neurodegenerative diseases such as, for example, Alzheimer""s disease, Parkinson""s disease, Amyotropic lateral sclerosis, AIDS-induced dementia and Huntington,s Chorea. The compounds are also indicated for use as antipsychotic, anti-emetic agents and as anticonvulsant agents, for example in the treatment of epilepsy. They are also of potential use as anxiolytic and antidepressant agents. The compounds are also indicated for use as analgesics, especially for the treatment of acute and chronic pain conditions associated with inflammation, cancer surgery and migraine.
The present invention also provides the use of a selective mnGluR1 antagonist for the manufacture of a medicament for the treatment of migraine. The selective mnGluR1 antagonist is preferably at least 10 fold selective for mGlur1 over mGluR5, more preferably at least 100 fold selective. The present invention also provides the use of a compound of formula (I) or formula (II) or a pharmaceutically-acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of migraine.
The present invention further provides the use of a compound of formula (I) or formula (II) or a pharmaceutically-acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of pain associated with migraine.
The ability of test compounds go treat migraine may be demonstrated as described in U.S. Pat. No. 5,817,671 (Oct. 6, 1998) U.S. Pat. No. 5,792,763 (Aug. 11, 1998) and J. Neurosci, Methods (1998), 81 (1, 2) 19-24.
The compound of Example 5, 3,6-Dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2-(4-methylcarbamoylbenzenesulphonyl)-2H-1,2-oxazine, has been found particularly effective.
In the method of invention the compounds are preferably administered in a pharmaceutical formulation comprising a pharmaceutically-acceptable diluent or carrier in association with a compound of formula (I), or a pharmaceutically-acceptable salt thereof.
The compounds may be administered by various routes, for example, by the oral or rectal route, topically or parenterally, for example by injection, and are usually employed in the form of a pharmaceutical composition. Such compositions form part of the present invention and are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound in association with a pharmaceutically-acceptable diluent or carrier. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, and/or enclosed with a carrier which may, for example, be in the form of a capsule, sachet, paper or other container. Where the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, as a solid or in a liquid medium, ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, injection solutions and suspensions and sterile packaged powders.
Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl- hydroxybenzoate, talc, magnesium stearate and mineral oil. Compositions in injectable form may, as it is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
When the compositions are formulated in unit dosage form, it is preferred that each unit dosage form contains from 5 mg to 500 mg, for example, from 15 mg to 200 mg. The term xe2x80x98unit dosage formxe2x80x99 refers to physically discrete units suitable as unit dosages for human subjects and animals. Each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
The active compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.5 to 300 mg/kg, more usually in the range of from 5 to 100 mg/kg. However, it will be understood that the amount administered will be determined by the physician in the light of the relevant circumstances, including the condition to be treated, the choice of compound to be administered and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.